Allogeneic hematopoietic stem cell transplantation (allo-HCT) is an established therapy for several hematologic malignancies. There exists considerable evidence that adoptive immunotherapy in the form of a donor T-cell mediated graft-versus-malignancy (GVM) is an important component of the curative potential of allo-HCT. Recently, non-myeloablative allogeneic transplantation (NHCT) has been utilized as a means of limiting the toxicity of conventional allo-HCT, thus increasing the accessibility of adoptive immunotherapy to cancer patients. However, cancer relapse remains an important cause of treatment failure and death following allo-HCT, and may be an even more significant hurdle following NHCT. Interaction of the CTLA-4 molecule on the T-cell surface with its ligands serves to down-regulate specific cell-mediated immune responses. Data from several pre-clinical models suggests that inhibition of CTLA-4 function may enhance anti-tumor immune responses. This proposal aims to assess delayed CTLA-4 blockade as a means of augmenting GVM in patients who have persistent or progressive malignancy following allo-HCT. Specifically, a three stage clinical trial will be performed to determine whether delayed CTLA-4 blockade, administered alone and in conjunction with donor lymphocyte infusion (DLI), is feasible following allo-HCT without induction of severe graft-versus-host disease (GVHD) or graft rejection, and whether preliminary evidence of augmentation of GVM can be documented. In vivo CTLA-4 blockade will be achieved through the use of a newly developed neutralizing human monoclonal antibody against CTLA-4 (MDX-CTLA-4) which will be administered at a single, fixed, biologically determined dose between day +100 and +370 following NHCT. The primary endpoint evaluated will be the incidence of grade 3/4 acute GVHD occurring within 90 days following CTLA-4 blockade. Other endpoints will include incidence of extensive stage chronic GVHD, incidence of graft rejection, disease response, progression-free and overall survival. Efficacy of the antibody will also be assessed by in vitro analysis of the reactivity of T-cells isolated from patients before and after CTLA-4 blockade, to malignant and non-malignant stimulator cells derived from the recipient.